Ras proteins belong to a family of related proteins that are present in all eukaryotic organisms from yeast to human (Santos et al., Structural and functional properties of ras proteins, FASEB J. 1989, 3(10), 2151-2163). Ras play a vital role in transducing extracellular cues into diverse cellular responses such as proliferation, apoptosis, and differentiation (Barbacid, M. Annual review of biochemistry, 1987, 56, 779). Ras operates as a molecular switch. In its resting (or “off”) state, it is found complexed with GDP. In its active (or “on”) state, it has GTP bound to it (Vetter et al., Science, 2001, 294, 1299). Ras becomes activated when growth factors bind to extracellular receptors which induce nucleotide exchange from GDP to GTP (Vetter et al., Science, 2001, 294, 1299). Ras proteins usually possess a slow intrinsic GTPase activity for hydrolysis of GTP to GDP, a reaction that can be enhanced by GTPase activating proteins (GAPs), converting Ras into an inactive signaling state. Mutations which diminish the GTPase activity or induce GAP insensitivity result in constitutively activated signaling pathways, leading to deregulated cell growth, inhibition of cell death, invasiveness, and induction of angiogenesis (Scheffzek et al., Science, 1997, 277, 333).
About 30% of all human cancers have been demonstrated to harbor activating Ras mutations (Bos, J. L. Cancer Research, 1989, 49, 4682; Prior et al., Cancer Research, 2012, 72, 2457). Of the oncogenic Ras family members (H, K, N), K-Ras is most often mutated with most cancer causing mutations located at codons 12, 13, and 61 (Bos, J. L. Cancer research, 1989, 49, 4682; Prior et al., Cancer Research, 2012, 72, 2457). G12C is a naturally occurring activating K-Ras mutation that is present in roughly 10-20% of all Ras-driven cancers with most cases involving lung, large bowel, pancreas, biliary tract, or uterus (Forbes et al., Nucleic Acids Research, 2011, 39, D945; Jones et al., British Journal of Cancer, 2004, 90, 1591). This mutation places a solvent-accessible cysteine adjacent to the active site, near the usual position of the gamma-phosphate of the native GTP and results in a constitutively activated K-Ras.
Despite more than 20 years of effort in industry and academia, targeting Ras has proven highly elusive (Downward, J. Nature reviews. Cancer, 2003, 3, 11; Gysin et al., Genes & Cancer, 2011, 2, 359; Wang et al., J. Bioorganic & medicinal chemistry letters, 2012, 22, 5766). Therefore, there is a need for new compounds to inhibit Ras for the treatment of diseases associated with aberrant Ras signaling, such as cancer.